Researchers from the faculty of medicine at the University of Ottawa and their international collaborators say they have shown proof-of-concept for a new therapeutic approach in treating tuberculosis (TB). The disease is caused by a bacterium, Mycobacterium tuberculosis, that infects the lungs and is highly transmissible when infected people cough or sneeze.
The team’s study ( “A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis”), published in Cell Chemical Biology, not only identifies a novel target for tuberculosis “host-directed therapy” and its mechanisms, but also delivers a newly designed chemical compound with drug-like properties that could be used to treat the illness in combination with existing antibiotics.
The compound synthesized by the scientists is derived from a natural product found in a flowering plant native to eastern North America. It was shown to be effective in boosting the function of macrophages and reducing TB bacteria inside the lungs of infected mice.
“Metal-dependent protein phosphatases (PPMs) have essential roles in a variety of cellular processes, including inflammation, proliferation, differentiation, and stress responses, which are intensively investigated in cancer and metabolic diseases. Targeting PPMs to modulate host immunity in response to pathogens is an ambitious proposition. The feasibility of such a strategy is unproven because development of inhibitors against PPMs is challenging and suffers from poor selectivity,” write the investigators.
“Combining a biomimetic modularization strategy with function-oriented synthesis, we design, synthesize and screen more than 500 pseudo-natural products, resulting in the discovery of a potent, selective, and non-cytotoxic small molecule inhibitor for PPM1A, SMIP-30. Inhibition of PPM1A with SMIP-30 or its genetic ablation (ΔPPM1A) activated autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, which restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in the lungs of infected mice.
SMIP-30 provides proof-of-concept that PPMs are druggable and promising targets for the development of host-directed therapies against tuberculosis.”
“The team was able to redesign this compound, so we now have a very specific, potent, non-toxic compound that works and functions beautifully to prompt our immune cells to kill the bug,” says Jim Sun, PhD, an assistant professor in the university’s department of biochemistry, microbiology, and Immunology. He is also the study’s corresponding author and the principal investigator of a university lab focusing on TB research.
Sun says the compound works by ramping up the autophagy process, a critical cellular pathway that can degrade foreign bacteria. Normally, TB bacteria is able to survive inside the body’s cells by disabling autophagy, but this new drug bypasses this and essentially super-powers macrophages to target the invaders.
More focus on phosphatases
Drug development has typically focused on kinases that play a key role in cell communication and serve as a sort of “on-switch” for cells’ antibacterial defense systems. But recent years have seen a marked increase of exploration focusing on phosphatases, enzymes that act as the “off-switch” and have historically been challenging for drug discovery, according to Sun.
The researchers believe their study provides compelling evidence that targeting phosphatases is now possible and promising. The team identified a host protein called PPM1A that’s exploited by the TB bacteria to hide and survive within the body’s immune cells. This protein is a phosphatase. They suggest that by inhibiting or blocking this off-switch, the ability of our cells to kill the bacteria can be successfully flipped on.
“Having personalized host-targeted medicine to treat [TB] cases would be huge,” says Sun, a cellular microbiologist by training.
Host-directed therapy could also be a major boon because tuberculosis is an outsized contributor to antimicrobial resistance, a significant global health threat that could cause 10 million deaths per year by 2050, according to a group of international experts.
“By harnessing the power of our immune cells to kill the bacteria, we bypass the bacteria’s natural ability to develop resistance against antibiotics,” notes Sun, who adds that the research team’s discoveries could be significant for therapeutic research and basic biology exploration.
“Our work has major implications not only for TB research and host-directed drug discovery, but also extends to researchers in all fields interested in regulation of autophagy and design of phosphatase inhibitors,” he explains. “This could cover a diverse range of medically relevant diseases such as other bacterial and viral infections, cancer, autoimmunity, neurodegenerative, and metabolic diseases.”
